Method for using 2-aryloxyalkylaminobenzoxazoles and 2-aryloxyalkylaminobenzothiazoles as H3 antagonists

ABSTRACT

The invention features methods of using pharmaceutically-active 2-aryloxyalkylaminobenzoxazoles and 2-aryloxyalkylaminobenzthiazoles and derivatives.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority from U.S. Provisional Application Ser.No. 60/194,071, filed on Mar. 31, 2000, and U.S. Provisional ApplicationSer. No. 60/272,291, filed on Feb. 28, 2001.

FIELD OF THE INVENTION

The invention relates to methods of using pharmaceutically-active fusedheterobicyclic compounds to treat or prevent disorders and conditionsmediated by the histamine H₃ receptor.

BACKGROUND

The histamine H₃ receptor is located as a presynaptic autoreceptor inthe central nervous system and as a presynaptic heteroreceptor onserotonergic, noradrenergic, dopaminergic, and cholinergic neurons. Thehistamine H₃ receptor is also located peripherally in tissues such asvascular smooth muscle cells.

Proposed uses of histamine H₃ antagonists include the treatment orprevention of dementia, Alzheimer's disease (Panula et al. Abstr.Society Neuroscience, 1995, 21:1977), epilepsy (Yokoyama et al. Eur. J.Pharmacol., 1993, 234:129), sleep/wake disorders (Lin et al., Br. Res.,1990, 523, 325; Monti et al., Eur. J. Pharmacol., 1991,205, 283)including narcolepsy, insomnia, and jet lag, eating disorders (Machidoriet al. Brain Research, 1992, 590:180), motion sickness, vertigo,attention deficit hyperactivity disorder, learning and memory disorders(Barnes et al. Abstr. Society Neuroscience, 1993,19:1813), schizophrenia(Schlickeret et al. Naunyn Schmiedeberg's Arch. Pharmacol., 1996,353:325), and sequelae associated with post-ischemic reperfusion andhypertension (Imamura et al., J. Pharmacol Expt. Ther., 1994, 271,1259).H₃ antagonists are also useful to treat or prevent neurogenicinflammation such as migraine (McLeod et al., Abstr. SocietyNeuroscience, 1996, 22, 2010), asthma (lchinose et al., Eur. J.Pharmacol., 989,174, 49), obesity, allergic rhinitis, substance abuse,bipolar disorders, manic disorders, and depression. Histamine H₃antagonists alone or in combination with a histamine H₁ antagonist arebelieved to be useful in the treatment of upper airway allergic responseor allergic rhinitis (see, e.g., U.S. Pat. Nos. 5,217,986, 5,352,707,and 5,869,479).

As noted, the prior art related to histamine H₃ ligands wascomprehensively reviewed recently (“The Histamine H ₃ Receptor-A Targetfor New Drugs”, Leurs, R., and Timmerman, H., (Editors), Elsevier,1998). Within this reference the medicinal chemistry of histamine H₃agonists and antagonists was reviewed (see Krause et al. and Phillips etal., respectively). Thus the importance of an imidazole moietycontaining only a single substitution in the 4 position was notedtogether with the deleterious effects of additional substitution onactivity. Particularly methylation of the imidazole ring at any of theremaining unsubstituted positions was reported to strongly decreaseactivity.

More recently several publications have described histamine H₃ ligandsthat do not contain an imidazole moiety. Examples include Ganellin et alArch. Pharm. (Weinheim,Ger.) 1998, 331, 395; Walczynski et al Arch.Pharm. (Weinheim,Ger.) 1999, 332, 389; Walczynski et al Farmaco 1999,684; Linney et al J. Med. Chem. 2000, 2362; U.S. Pat. No. 5,352,707; PCTApplication WO99/42458, published Aug. 26,1999; and European PatentApplication 0978512, published on Feb. 9, 2000.

SUMMARY OF THE INVENTION

The invention features the use of the compounds of formula (I) for thetreatment and/or prevention of diseases and conditions mediated by thehistamine 3 (H₃) receptor.

R is O or S;

R₁ is H, C₁₋₄ alkyl, C₁₋₄ alkoxy, Br, Cl, or l;

R₂ and R₃ are H or —O—(CH₂)_(m)—NR₄R₅, wherein one of R₂ and R₃ is H andthe other is —O—(CH₂)_(m)—NR₄R₅, when R₃ is —O—(CH₂)_(m)—NR₄R₅, R₂ isindependently H, halogen, C₁₋₄ alkyl, or C₁₋₄ alkoxy;

R₄ and R₅ are the same or different, and are C₁₋₅ alkyl, C cycloalkyl,benzyl, benzyl substituted by C₁₋₄ alkyl, C₁₋₄ alkoxy, Br, Cl, l, or R₄and R₅ together with N are piperidyl, pyrrolidyl, imidazolyl, orN-substituted piperazyl, wherein the substituent is C₁₋₄ alkyl, phenyl,or phenyl substituted with C₁₋₃ alkoxy; n is 0 or 1; m is 2-6; with theprovisos that when at least one of R and R₁ is Ar; and both of R and R₁are not Ar;

or a pharmaceutically acceptable salt, ester, or amide thereof.

Many of the compounds are disclosed generically in U.S. Pat. No.4,861,897. These compounds were first identified as having antisecretoryproperties. Additional features of the invention are disclosed in thefollowing description and examples, and in the appended claims.

DETAILED DESCRIPTION

The invention features pharmaceutically active phenyl-substitutedimidazopyridines and methods of making and using them. The descriptionis organized as follows:

A. Terms

B. Compounds

C. Synthetic Methods

D. Uses

E. Synthetic Chemical Examples

F. Biological Examples

G. Other Embodiments

H. claims

A. Terms

The following terms are defined below and by their usage throughout thisdisclosure.

“Alkyl” includes straight chain and branched hydrocarbons with at leastone hydrogen removed to form a radical group. Alkyl groups includemethyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl,1-methylpropyl, pentyl, isopentyl, sec-pentyl, hexyl, heptyl, octyl, andso on.

“Alkoxy” includes a straight chain or branched alkyl group with aterminal oxygen linking the alkyl group to the rest of the molecule.Alkoxy includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy,pentoxy and so on.

“halo” or “halogen” includes fluoro, chloro, bromo, and iodo, andpreferably fluoro or chloro.

“patient” or “subject” includes mammals such as humans and animals(dogs, cats, horses, rats, rabbits, mice, non-human primates) in need ofobservation, experiment, treatment or prevention in connection with therelevant disease or condition. Preferably, the patient is a human.

“composition” includes a product comprising the specified ingredients inthe specified amounts as well as any product which results directly orindirectly from combinations of the specified ingredients in thespecified amounts.

Concerning the various radicals in this disclosure and in the claims,two general remarks are made. The first remark concerns valency. As withall hydrocarbon radicals, whether saturated, unsaturated or aromatic,and whether or not cyclic, straight chain, or branched, and alsosimilarly with all heterocyclic radicals, each radical includessubstituted radicals of that type and monovalent, bivalent, andmultivalent radicals as indicated by the context of the claims. Thecontext will indicate that the substituent is an alkylene or hydrocarbonradical with at least two hydrogen atoms removed (bivalent) or morehydrogen atoms removed (multivalent).

Second, radicals or structure fragments as defined herein are understoodto include substituted radicals or structure fragments. Using “alkyl” asan example, “alkyl” should be understood to include substituted alkylhaving one or more substitutions, such as between 1 and 5, 1 and 3, or 2and 4 substituents. The substituents may be the same (dihydroxy,dimethyl), similar (chlorofluoro), or different (chlorobenzyl- oraminomethyl-substituted). Examples of substituted alkyl includehaloalkyl (such as fluoromethyl, chloromethyl, difluoromethyl,perchloromethyl, 2-bromoethyl, and 3-iodocyclopentyl), hydroxyalkyl,aminoalkyl, nitroalkyl, alkylalkyl, and so on.

B. Compounds

One aspect of the invention features compounds of formula (I) asdescribed in the Summary section above.

Preferred compounds of formula (I) include those compounds wherein: (a)R₂ is H; (b) R₃ is H; (c) R is O; (d) R₁ is H; (e) R is S; (f) n is 1;(g) n is 0; (h) NR₄R₅ is a cyclic radical; (i) (h) wherein said cyclicradical is piperidyl or pyrrolinyl; (j) each of R₄ and R₅ isindependently selected from ethyl, propyl, isopropyl, and butyl,including n-butyl, sec-butyl, tert-butyl, and isobutyl; (k) m is 2, 3,or 4, and more preferably wherein m is 3 or 4; (l) m is 3; (m) R₁ is H,methyl, methoxy, Br, Cl, or l; (n) R₂ is H, halogen, methyl, or methoxy,and preferably methyl; (o) or combinations thereof.

Additional preferred compounds include those wherein: R₁ is H, methyl,methoxy, Br, Cl, or l; each of R₄ and R₅ is independently selected fromethyl, propyl, isopropyl, and butyl, or together with N are piperidyl orpyrrolinyl; m is 3 or 4; and each R₂ is H, halogen, methyl, or methoxy.

Preferred compounds include:(E)-2-[2-(3-dibutylaminopropoxyphenyl)-ethenyl]benzoxazole;(E)-2-[2-[3-[3-(4-methylpiperazino)propoxy]-phenyl]ethenyl]benzoxazole;(E)-2-[2-(3-dipropylaminopropoxyphenyl)ethenyl]-benzoxazole;(E)-2-[2-(3-(1H-imidazol-1-yl)propoxyphenyl)ethenyl]-benzoxazole;(E)-2-[2-(3-dipropylaminobutoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(3-(1H-imidazol-1-yl)butoxyphenyl)ethenyl]benzoxazole; and(E)-2-[2-(3-(1H-imidazol-1-yl)butoxyphenyl)ethenyl]-6-methoxybenzoxazole;and acid addition salts thereof.

Preferred compounds also include:(E)-2-[2-(4-dibutylaminopropoxy-phenyl)ethenyl]benzoxazole;(E)-2-[2-(4-dipropylaminopropoxyphenyl)ethenyl]-benzoxazole;(E)-2-[2-(4-(1H-imidazol-1-yl)propoxyphenyl)ethenyl]-benzoxazole;(E)-2-[2-(4-diethylaminopropoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-[4-(3-Piperidinopropoxy)phenyl]ethenyl]benzoxazole;(E)-2-[2-[4-(3-methylbenzylaminopropoxy)phenyl]ethenyl]benzoxazole;(E)-2-[2-[4-(2-methoxyphenyl)piperazinopropoxyphenyl]ethenyl]benzoxazole;(E)-2-[2-(4-dibutylaminopropoxyphenyl)ethenyl]-5-methylbenzoxazole;(E)-2-[2-(4-dibutylaminopropoxyphenyl)ethenyl]-6-methoxybenzoxazole;(E)-2-[2-(4-dibutylaminoethoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(4-dibutylamino-butoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(4-piperidinobutoxyphenyl)-ethenyllbenzoxazole;(E)-2-[2-(4-dipropylaminobutoxyphenyl)ethenyl]-benzoxazole;(E)-2-[2-(4-(1H-imidazol-1-yl)butoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(4-diethylaminobutoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(4-pyrrolidinobutoxyphenyl)ethenyl]benzoxazole; and(E)-2-[2-(4-(1H-imidazol-1-yl)pentoxyphenyl)ethenyl]benzoxazole; andacid addition salts thereof.

Additional preferred compounds include:(E)-2-[2-(3-chloro-4-dipropylaminobutoxyphenyl)ethenyl]benzoxazole,(E)-2-[2-(3,5-dimethoxy-4-dipropylaminopropoxyphenyl)ethenyl]benzoxazoleand(E)-2-[2-(3,5-dimethyl-4-dipropylaminopropoxyphenyl)ethenyl]benzoxazole;and acid addition salts thereof.

More preferred compounds include:(E)-2-[2-(4-Piperidinopropoxy-phenyl)ethenyl]benzothiazole;(E)-2-[2-[4-(3-Piperidinopropoxy)phenyl]-ethenyl]benzoxazole;(E)-2-[2-(4-Piperidinobutoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(4-Diethylaminobutoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(4-Diethylaminopropoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(4-Pyrrolinobutoxy-phenyl)ethenyl]benzoxazole;E)-2-[2-(4-Dibutylaminobutoxyphenyl)-ethenyl]benzoxazole; and2-(4-Dipropylaminopropoxyphenyl)benzothiazole and pharmaceuticallyacceptable salts thereof.

Other examples of compounds, and methods of making them, are provided inthe examples below.

C. Synthetic Methods

The invention provides methods of making the disclosed compoundsaccording to traditional organic synthetic methods as well as matrix orcombinatorial synthetic methods. Traditional organic synthetic methodsare described in U.S. Pat. No. 4,861,897, which is incorporated byreference in its entirety. Further guidance is found in ChemicalExamples 1-8 below.

C. Uses

According to the invention, the disclosed compounds and compositions areuseful for the amelioration of symptoms associated with, the treatmentof, and/or the prevention of, the following conditions and diseases, orsymptoms associated with them: dementia, Alzheimer's disease,narcolepsy, eating disorders, motion sickness, vertigo, attentiondeficit hyperactivity disorder, learning and memory disorders,schizophrenia, mild cognitive impairment, upper airway allergic response(allergic rhinitis), insomnia, jet lag, obesity, asthma, neurogenicinflammation, substance abuse, bipolar disorders, manic disorders, anddepression. The invention also features pharmaceutical compositions,which include, without limitation, one or more of the disclosedcompounds, and a pharmaceutically acceptable carrier or excipient.

1. Dosages

Those skilled in the art will be able to determine, according to knownmethods, the appropriate dosage for a patient, taking into accountfactors such as age, weight, general health, the type of symptomsrequiring treatment, and the use of other medications. An effectiveamount means that amount of pharmaceutical reagent (such as a prodrug,metabolic precursor, or active compound) that elicits the biological ormedical response desired. In general, a therapeutically effective amountwill be between 0.01 and 1000 mg/kg per day, preferably between 0.01 and250 mg/kg body weight, and daily dosages will be between 0.50 and 5000mg for an adult subject of normal weight. Capsules, tablets or otherformulations (such as liquids and film-coated tablets) may be of between0.20 and 100 mg, such as 0.20, 0.50, 1, 2, 3, and 10 mg can beadministered according to the disclosed methods.

2. Formulations

Dosage unit forms include tablets, capsules, pills, powders, granules,aqueous and nonaqueous oral solutions and suspensions, and parenteralsolutions packaged in containers adapted for subdivision into individualdoses. Dosage unit forms can also be adapted for various methods ofadministration, including controlled release formulations, such assubcutaneous implants. Administration methods include oral, rectal,parenteral (intravenous, intramuscular, subcutaneous), intracisternal,intravaginal, intraperitoneal, intravesical, local (drops, powders,ointments, gels or cream), and by inhalation (a buccal or nasal spray)as appropriate depending on the overall health and condition of thepatient as determined by a physician or veterinary doctor.

Parenteral formulations include pharmaceutically acceptable aqueous ornonaqueous solutions, dispersion, suspensions, emulsions, and sterilepowders for the preparation thereof. Examples of carriers include water,ethanol, polyols (propylene glycol, polyethylene glycol), vegetableoils, and injectable organic esters such as ethyl oleate. Fluidity canbe maintained by the use of a coating such as lecithin, a surfactant, ormaintaining appropriate particle size. Carriers for solid dosage formsinclude (a) fillers or extenders, (b) binders, (c) humectants, (d)disintegrating agents, (e) solution retarders, (f) absorptionaccelerators, (g) adsorbants, (h) lubricants, (i) buffering agents, and(j) propellants.

Compositions may also contain adjuvants such as preserving, wetting,emulsifying, and dispensing agents; antimicrobial agents such asparabens, chlorobutanol, phenol, and sorbic acid; isotonic agents suchas a sugar or sodium chloride; absorption-prolonging agents such asaluminum monostearate and gelatin; and absorption-enhancing agents.

3. Combination Therapy

The present invention also provides compositions and methods useful forthe treatment of disorders or conditions modulated, preferablyantagonized, by the histamine H₃ receptor in combination with compoundsthat modulate other receptors including, but not limited to, histamineH₁ and histamine H₂ receptors. The present invention includes compoundsand compositions useful in methods of combination therapy for thetreatment of diseases or conditions modulated by the histamine H₃receptor in combination with compounds that are selective serotoninre-uptake inhibitors (SSRIs), such as PROZACTM, or are selectivenorepinephrine uptake inhibitors. Such combination methods include (a)administering the two or more pharmaceutical agents separatelyformulated and at separate times, and (b) administering the two or moreagents simultaneously in a single formulation or in separateformulations administered more or less at the same time. For example,one aspect is a method of treatment comprising administering at leastone histamine H₃ receptor modulating compound disclosed herein andadministering at least one compound selected from a histamine H₁receptor modulating compound, a histamine H₂ receptor modulatingcompound, a selective serotonin reuptake inhibitor (such as PROZAC™), ora selective norepinephrine uptake inhibiting compound.

4. Related Compounds

The invention provides the disclosed compounds and closely related,pharmaceutically acceptable forms of the disclosed compounds, such assalts, esters, amides, acids, hydrates or solvated forms thereof; maskedor protected forms; and racemic mixtures, or enantiomerically oroptically pure forms.

Pharmaceutically acceptable salts, esters, and amides includecarboxylate salts (e.g., C₁₋₈, alkyl, cycloalkyl, aryl, heteroaryl, ornon-aromatic heterocyclic) amino acid addition salts, esters, and amideswhich are within a reasonable benefit/risk ratio, pharmacologicallyeffective and suitable for contact with the tissues of patients withoutundue toxicity, irritation, or allergic response. Representative saltsinclude hydrobromide, hydrochloride, sulfate, bisulfate, nitrate,acetate, oxalate, valerate, oleate, palmitate, stearate, laurate,borate, benzoate, lactate, phosphate, tosylate, citrate, maleate,fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate,lactiobionate, and laurylsulfonate. These may include alkali metal andalkali earth cations such as sodium, potassium, calcium, and magnesium,as well as non-toxic ammonium, quaternary ammonium, and amine cationssuch as tetramethyl ammonium, methylamine, trimethylamine, andethylamine. See example, S. M. Berge, et al., “Pharmaceutical Salts,” J.Pharm. Sci., 1977, 66:1-19 which is incorporated herein by reference.Representative pharmaceutically acceptable amides of the inventioninclude those derived from ammonia, primary C₁₋₆ alkyl amines andsecondary di (C₁₋₆ alkyl) amines. Secondary amines include 5- or6-membered heterocyclic or heteroaromatic ring moieties containing atleast one nitrogen atom and optionally between 1 and 2 additionalheteroatoms. Preferred amides are derived from ammonia, C₁₋₃alkylprimary amines, and di (C₁₋₂ alkyl)amines. Representativepharmaceutically acceptable esters of the invention include C₁₋₇alkyl,C₅₋₇ cycloalkyl, phenyl, and phenyl(C₁₋₆)alkyl esters. Preferred estersinclude methyl esters.

The invention also includes disclosed compounds having one or morefunctional groups (e.g., hydroxyl, amino, or carboxyl) masked by aprotecting group. See, e.g., Greene and Wuts, Protective Groups inOrganic Synthesis, 3^(rd) ed., (1999) John Wiley & Sons, NY. Some ofthese masked or protected compounds are pharmaceutically acceptable;others will be useful as intermediates. Synthetic intermediates andprocesses disclosed herein, and minor modifications thereof, are alsowithin the scope of the invention.

Hydroxyl Protecting Groups

Protection for the hydroxyl group includes methyl ethers, substitutedmethyl ethers, substituted ethyl ethers, substitute benzyl ethers, andsilyl ethers.

Substituted Methyl Ethers

Examples of substituted methyl ethers include methyoxymethyl,methylthiomethyl, t-butylthiomethyl, (phenyidimethylsilyl)methoxymethyl,benzyloxymethyl, p-methoxybenzyloxymethyl, (4-methoxyphenoxy)methyl,guaiacolmethyl, t-butoxymethyl, 4-pentenyloxymethyl, siloxymethyl,2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl,bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl,tetrahydropyranyl, 3-bromotetrahydropyranyl, tetrahydrothiopyranyl,1-methoxycyclohexyl, 4-methoxytetrahydropyranyl,4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranylS,S-dioxido, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl,1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl and2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl.

Substituted Ethyl Ethers

Examples of substituted ethyl ethers include 1-ethoxyethyl,1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl,1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl,2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl,t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, andbenzyl.

Substituted Benzyl Ethers

Examples of substituted benzyl ethers include p-methoxybenzyl,3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl,2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2- and 4-picolyl,3-methyl-2-picolyl N-oxido, diphenylmethyl, p, p′-dinitrobenzhydryl,5-dibenzosuberyl, triphenylmethyl, α-naphthyidiphenylmethyl,p-methoxyphenyidiphenylmethyl, di(p-methoxyphenyl)phenylmethyl,tri(p-methoxyphenyl)methyl, 4-(4′-bromophenacyloxy)phenyldiphenylmethyl,4,4′,4″-tris(4,5-dichlorophthalimidophenyl)methyl,4,4′,4″-tris(levulinoyloxyphenyl)methyl,4,4′,4″-tris(benzoyloxyphenyl)methyl, 3-(Imidazol-1-ylmethyl)bis(4′,4″-dimethoxyphenyl)methyl, 1,1-bis(4-methoxyphenyl)-1′-pyrenylmethyl,9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl,1,3-benzodithiolan-2-yl, and benzisothiazolyl S,S-dioxido.

Silyl Ethers

Examples of silyl ethers include trimethylsilyl, triethylsilyl,triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl,dimethylthexylsilyl, t-butyidimethylsilyl, t-butyldiphenylsilyl,tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl,and t-butylmethoxyphenylsilyl.

Esters

In addition to ethers, a hydroxyl group may be protected as an ester.Examples of esters include formate, benzoylformate, acetate,chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate,methoxyacetate, triphenylmethoxyacetate, phenoxyacetate,p-chlorophenoxyacetate, p-P-phenylacetate, 3-phenylpropionate,4-oxopentanoate(levulinate), 4,4-(ethylenedithio)pentanoate, pivaloate,adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate,2,4,6-trimethylbenzoate(mesitoate)

Carbonates Examples of carbonate protecting groups include methyl,9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl,2-(phenylsulfonyl)ethyl, 2-(triphenylphosphonio)ethyl, isobutyl, vinyl,allyl, p-nitrophenyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl,o-nitrobenzyl, p-nitrobenzyl, S-benzyl thiocarbonate,4-ethoxy-1-naphthyl, and methyl dithiocarbonate.

Assisted Cleavage

Examples of assisted cleavage include 2-iodobenzoate, 4-azidobutyrate,4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate,2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl carbonate,4-(methylthiomethoxy)butyrate, and 2-(methylthiomethoxymethyl)benzoate.

Miscellaneous Esters

Examples of miscellaneous esters include2,6-dichloro-4-methylphenoxyacetate,2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate,2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate,isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate(tigloate),o-(methoxycarbonyl)benzoate, p-P-benzoate, α-naphthoate, nitrate, alkylN,N,N′,N′-tetramethylphosphorodiamidate, N-phenylcarbamate, borate,dimethylphosphinothioyl, and 2,4-dinitrophenylsulfenate

Sulfonates

Examples of sulfonates include sulfate, methanesulfonate(mesylate),benzylsulfonate, and tosylate.

Protection for 1,2- and 1,3-Diols

Cyclic Acetals and Ketals

Examples of cyclic acetals and ketals include methylene, ethylidene,1-t-butylethylidene, 1-phenylethylidene, (4-methoxyphenyl)ethylidene,2,2,2-trichloroethylidene, acetonide (isopropylidene), cyclopentylidene,cyclohexylidene, cycloheptylidene, benzylidene, p-methoxybenzylidene,2,4-dimethoxybenzylidene, 3,4-dimethoxybenzylidene, and2-nitrobenzylidene.

Cyclic Ortho Esters

Examples of cyclic ortho esters include methoxymethylene,ethoxymethylene, dimethoxymethylene, 1-methoxyethylidene,1-ethoxyethylidine, 1,2-dimethoxyethylidene, α-methoxybenzylidene,1-(N,N-dimethylamino)ethylidene derivative,α-(N,N-dimethylamino)benzylidene derivative, and 2-oxacyclopentylidene.

Silyl Derivatives

Examples of silyl derivatives include di-t-butylsilylene group, and1,3-(1,1,3,3-tetraisopropyldisiloxanylidene) derivative.

Amino Protecting Groups

Protection for the amino group includes carbamates, amides, and special—NH protective groups.

Examples of carbamates include methyl and ethyl carbamates, substitutedethyl carbamates, assisted cleavage carbamates, photolytic cleavagecarbamates, urea-type derivatives, and miscellaneous carbamates.

Carbamates

Examples of methyl and ethyl carbamates include methyl and ethyl,9-fluorenylmethyl, 9-(2-sulfo)fluorenylmethyl,9-(2,7-dibromo)fluorenylmethyl,2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl,and 4-methoxyphenacyl.

Substituted Ethyl

Examples of substituted ethyl carbamates include 2,2,2-trichloroethyl,2-trimethylsilylethyl, 2-phenylethyl, 1-(1-adamantyl)-1-methylethyl,1,1-dimethyl-2-haloethyl, 1,1-dimethyl-2,2- dibromoethyl,1,1-dimethyl-2,2,2-trichloroethyl, 1-methyl-1-(4-biphenylyl)ethyl,1-(3,5-di-t-butylphenyl)-1-methylethyl, 2-(2′- and 4′-pyridyl) ethyl,2-(N,N-dicycl ohexylcarboxamido)ethyl, t-butyl, 1-adamantyl, vinyl,allyl, 1-isopropylallyl, cinnamyl, 4-nitrocinnamyl, 8-quinolyl,N-hydroxypiperidinyl, alkyldithio, benzyl, p-methoxybenzyl,p-nitrobenzyl, p-bromobenzyl, p-chlorobenzyl, 2,4-dichlorobenzyl,4-methylsulfinylbenzyl, 9-anthrylmethyl and diphenylmethyl.

Assisted Cleavage

Examples of assisted cleavage include 2-methylthioethyl,2-methylsulfonylethyl, 2-(p-toluenesulfonyl)ethyl,[2-(1,3-dithianyl)]methyl, 4-methylthiophenyl, 2,4-dimethylthiophenyl,2-phosphonioethyl, 2-triphenylphosphonioisopropyl,1,1-dimethyl-2-cyanoethyl, m-chloro-p-acyloxybenzyl,p-(dihydroxyboryl)benzyl, 5-benzisoxazolylmethyl, and2-(trifluoromethyl)-6-chromonylmethyl.

Photolytic Cleavage

Examples of photolytic cleavage include m-nitrophenyl,3,5-dimethoxybenzyl, o-nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl, andphenyl(o-nitrophenyl)methyl.

Urea-type Derivatives

Examples of urea-type derivatives include phenothiazinyl-(10)-carbonylderivative, N′-p-toluenesulfonylaminocarbonyl, andN′-phenylaminothiocarbonyl.

Miscellaneous Carbamates

Examples of miscellaneous carbamates include t-amyl, S-benzylthiocarbamate, p-cyanobenzyl, cyclobutyl, cyclohexyl, cyclopentyl,cyclopropyl methyl, p-decyloxybenzyl, diisopropyl methyl,2,2-dimethoxycarbonylvinyl, o-(N,N-dimethylcarboxamido)benzyl,1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl, 1,1-dimethylpropynyl,di(2-pyridyl)methyl, 2-furanylmethyl, 2-iodoethyl, isobornyl, isobutyl,isonicotinyl, p-(p′-methoxyphenylazo)benzyl, 1-methylcyclobutyl,1-methylcyclohexyl, 1-methyl-1-cyclopropylmethyl,1-methyl-1-(3,5-dimethoxyphenyl)ethyl,1-methyl-1-(p-phenylazophenyl)ethyl, 1-methyl-1-phenylethyl,1-methyl-1-(4-pyridyl)ethyl, phenyl, p-(phenylazo)benzyl,2,4,6-tri-t-butylphenyl, 4-(trimethylammonium)benzyl, and2,4,6-trimethylbenzyl.

Examples of amides include:

Amides

N-formyl, N-acetyl, N-chloroacetyl, N-trichloroacetyl,N-trifluoroacetyl, N-phenylacetyl, N-3-phenylpropionyl, N-picolinoyl,N-3-pyridylcarboxamide, N-benzoylphenylalanyl derivative, N-benzoyl,N-p-phenylbenzoyl.

Assisted Cleavage

N-o-nitrophenylacetyl, N-o-nitrophenoxyacetyl, N-acetoacetyl,(N′-dithiobenzyloxycarbonylamino)acetyl, N-3-(p-hydroxyphenyl)propionyl,N-3-(o-nitrophenyl)propionyl, N-2-methyl-2-(o-nitrophenoxy)propionyl,N-2-methyl-2-(o-phenylazophenoxy)propionyl, N-4-chlorobutyryl,N-3-methyl-3-nitrobutyryl, N-o-nitrocinnamoyl, N-acetylmethioninederivative, N-o-nitrobenzoyl, N-o-(benzoyloxymethyl)benzoyl, and4,5-diphenyl-3-oxazolin-2-one.

Cyclic Imide Derivatives

N-phthalimide, N-dithiasuccinoyl, N-2,3-diphenylmaleoyl,N-2,5-dimethylpyrrolyl, N-1,1,4,4-tetramethyldisilylazacyclopentaneadduct, 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one,5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, and1-substituted 3,5-dinitro-4-pyridonyl.

Special-NH Protective Groups

Examples of special NH protective groups include

N-Alkyl and N-Aryl Amines

N-methyl, N-allyl, N-[2-(trimethylsilyl)ethoxy]methyl,N-3,-acetoxypropyl, N-(1-isopropyl4-nitro-2-oxo-3-pyrrolin-3-yl),quaternary ammonium salts, N-benzyl, N-di(4-methoxyphenyl)methyl,N-5-dibenzosuberyl, N-triphenylmethyl,N-(4-methoxyphenyl)diphenylmethyl, N-9-phenylfluorenyl,N-2,7-dichloro-9-fluorenylmethylene, N-ferrocenylmethyl, andN-2-picolylamine N′-oxide.

Imine Derivatives

N-1,1-dimethylthiomethylene, N-benzylidene, N-p-methoxybenzylidene,N-diphenylmethylene, N-[(2-pyridyl)mesityl]methylene, andN-(N′,N′-dimethylaminomethylene).

Protection for the Carbonyl Group

Acyclic Acetals and Ketals

Examples of acyclic acetals and ketals include dimethyl,bis(2,2,2-trichloroethyl), dibenzyl, bis(2-nitrobenzyl) and diacetyl.

Cyclic Acetals and Ketals

Examples of cyclic acetals and ketals include 1,3-dioxanes,5-methylene-1,3-dioxane, 5,5-dibromo-1,3-dioxane,5-(2-pyridyl)-1,3-dioxane, 1,3-dioxolanes, 4-bromomethyl-1,3-dioxolane,4-(3-butenyl)-1,3-dioxolane, 4-phenyl-1,3-dioxolane,4-(2-nitrophenyl)-1,3-dioxolane, 4,5-dimethoxymethyl-1,3-dioxolane,O,O′-phenylenedioxy and 1,5-dihydro-3H-2,4-benzodioxepin.

Acyclic Dithio Acetals and Ketals

Examples of acyclic dithio acetals and ketals include S,S′-dimethyl,S,S′-diethyl, S,S′-dipropyl, S,S′-dibutyl, S,S′-dipentyl, S,S′-diphenyl,S,S′-dibenzyl and S,S′-diacetyl.

Cyclic Dithio Acetals and Ketals

Examples of cyclic dithio acetals and ketals include 1,3-dithiane,1,3-dithiolane and 1,5-dihydro-3H-2,4-benzodithiepin.

Acyclic Monothio Acetals and Ketals

Examples of acyclic monothio acetals and ketals includeO-trimethylsilyl-S-alkyl, O-methyl-S-alkyl or -S-phenyl andO-methyl-S-2-(methylthio)ethyl.

Cyclic Monothio Acetals and Ketals

Examples of cyclic monothio acetals and ketals include 1,3-oxathiolanes.

Miscellaneous Derivatives

O-Substituted Cyanohydrins

Examples of O-substituted cyanohydrins include O-acetyl,O-trimethylsilyl, O-1-ethoxyethyl and O-tetrahydropyranyl.

Substituted Hydrazones

Examples of substituted hydrazones include N,N-dimethyl and2,4-dinitrophenyl.

Oxime Derivatives

Examples of oxime derivatives include O-methyl, O-benzyl andO-phenylthiomethyl.

Imines

Substituted Methylene Derivatives, Cyclic Derivatives

Examples of substituted methylene and cyclic derivatives includeoxazolidines, 1-methyl-2-(1′-hyd roxyalkyl)imidazoles,N,N′-dimethylimidazolidines, 2,3-dihydro-1,3-benzothiazoles,diethylamine adducts, and methylaluminumbis(2,6-di-t-butyl4-methylphenoxide)(MAD)complex.

Monoprotection of Dicarbonyl Compounds

Selective Protection Of α-and β-Diketones

Examples of selective protection of α-and β-diketones include enamines,enol acetates, enol ethers, methyl, ethyl, 1-butyl, piperidinyl,morpholinyl, 4-methyl-1,3-dioxolanyl, pyrrolidinyl, benzyl, S-butyl, andtrimethylsilyl.

Cyclic Ketals, Monothio and Dithio Ketals

Examples of cyclic ketals, monothio and dithio ketals includebismethylenedioxy derivatives and tetramethylbismethylenedioxyderivatives.

Protection for the Carboxyl Group

Esters

Examples of esters include the following.

Substituted Methyl Esters

Examples of substituted methyl esters include 9-fluorenylmethyl,methoxymethyl, methylthiomethyl, tetrahyd ropyranyl, tetrahydrofuranyl,methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, benzyloxymethyl,phenacyl, p-bromophenacyl, β-methylphenacyl, p-methoxyphenacyl,carboxamidomethyl, and N-phthalimidomethyl.

2-Substituted Ethyl Esters

Examples of 2-substituted ethyl esters include 2,2,2-trichloroethyl,2-haloethyl, ω-chloroalkyl, 2-(trimethylsilyl)ethyl, 2-methylthioethyl,1,3-dithianyl-2-methyl, 2-(p-nitrophenylsulfenyl)ethyl,2-(p-toluenesulfonyl)ethyl, 2-(2′-pyridyl)ethyl,2-(diphenylphosphino)ethyl, 1-methyl-1-phenylethyl, t-butyl,cyclopentyl, cyclohexyl, allyl, 3-buten-1-yl,4-(trimethylsilyl)-2-buten-1-yl, cinnamyl, α-methylcinnamyl, phenyl,p-(methylmercapto)phenyl and benzyl.

Substituted Benzyl Esters

Examples of substituted benzyl esters include triphenylmethyl,diphenylmethyl, bis(o-nitrophenyl)methyl, 9-anthrylmethyl,2-(9,10-dioxo)anthrylmethyl, 5-dibenzosuberyl, 1-pyrenylmethyl,2-(trifluoromethyl)-6-chromylmethyl, 2,4,6-trimethylbenzyl,p-bromobenzyl, o-nitrobenzyl, p-nitrobenzyl, p-methoxybenzyl,2,6-dimethoxybenzyl, 4-(methylsulfinyl)benzyl, 4-sulfobenzyl, piperonyl,4-picolyl and p-P-benzyl.

Silyl Esters

Examples of silyl esters include trimethylsilyl, triethylsilyl,t-butyldimethylsilyl, 1-propyidimethylsilyl, phenyidimethylsilyl anddi-t-butylmethylsilyl.

Activated Esters

Examples of activated esters include thiols.

Miscellaneous Derivatives

Examples of miscellaneous derivatives include oxazoles,2-alkyl-1,3-oxazolines, 4-alkyl-5-oxo-1,3-oxazolidines,5-alkyl-4-oxo-1,3-dioxolanes, ortho esters, phenyl group andpentaaminocobalt(III) complex.

Stannyl Esters

Examples of stannyl esters include triethylstannyl andtri-n-butylstannyl.

Amides and Hydrazides

Amides

Examples of amides include N,N-dimethyl, pyrrolidinyl, piperidinyl,5,6-dihydrophenanthridinyl, o-nitroanilides, N-7-nitroindolyl,N-8-Nitro-1,2,3,4-tetrahydroquinolyl, and p-P-benzenesulfonamides.

Hydrazides

Examples of hydrazides include N-phenyl and N,N′-diisopropyl hydrazides.

D. Synthetic Chemical Examples

Additional experimental descriptions of the compounds of the inventionare found in the Examples of U.S. Pat. No. 4,861,897, incorporatedherein by reference in its entirety. Examples 3, 4, 6, 7, 8, and 9 belowcorrespond to Examples 1,2, 13, 7, 8, and 14 of the '897 patent,respectively, and are provided as general guidance.

EXAMPLE 1 (E)-2-[2-(4-Dibutylaminopropoxyphenyl)ethenyl]benzoxazole

To a suspension of sodium hydride (50% in oil, 3.9 g, 82 mmol) indimethylformamide (100 ml) was added p-hydroxybenzaldehyde (5.0 g, 41mmol). The mixture was stirred at room temperature under an atmosphereof nitrogen for one hour, then treated dropwise with1-bromo-3-chloropropane (8.1 ml, 82 mmol). The mixture was stirred atroom temperature for 12 hours, quenched with methanol and filteredthrough Celite. The filtrate was dissolved in diethyl ether (500 ml),washed with water (3×200 ml) and dried over Na₂ SO₄. The ether layer wasconcentrated to give 6.1 g (80% yield) of 4-chloropropoxybenzaldehyde asa yellow liquid. ¹H NMR (CDCl₃): δ 9.95 (s, 1H), 7.85 (d, J=8.1 Hz, 2H),7.01 (d, J=8.1 Hz, 2H), 4.21 (t, J=5 Hz, 2H), 3.81 (t, J=5 Hz, 2H), 1.26(m, 2H).

To a solution of this product (5.0 g, 25 mmol) and 2-methylbenzoxazole(3.1 ml, 25 mmol) in dimethylsulfoxide (25 ml) was added a 50% aqueoussodium hydroxide solution (15 ml). The solution was stirred at roomtemperature for 24 hours, diluted with ice water (1 L), and theresulting precipitate was collected by filtration. The precipitate waswashed with water and dried in vacuo to give(E)-2-[2-(4-chloropropoxyphenyl)ethenyl]benzoxazole (C) (6.4 g, 79%yield) as a yellow solid, mp 82°-83° C. IR(KBr): 1600 cm⁻¹ MS: 313(M⁺).¹H NMR (CDCl₃): δ 7.88-6.79 (m, 10H), 4.19 (t, J=5 Hz, 2H), 3.79 (t, J=5Hz, 2H), 2.31 (m, 2H).

Theor. C₁₈H₁₆ NO₂ Cl: C, 68.90; H, 5.14; N, 4.46. Found: C, 69.20; H,5.46; N, 4.27.

A solution of this product (6.0 g, 19 mmol) in 60 ml of dibutylamine washeated to 150° C. for 12 hours. The excess dibutylamine was removed bydistillation and the resulting oil was purified by flash chromatography(SiGel, 9:1 CHCl₃ —MeOH) to give 5.8 g (75% yield) of the free base ofthe title compound. The HCl salt was prepared by the addition ofconcentrated hydrochloric acid to a solution of the free base inmethanol, concentrated, and recrystallized from acetone to give the HClsalt of the title compound as a yellow solid, mp 153°-154° C. IR(KBr):3400,1595 cm⁻¹ MS: 406(MH⁺). ¹H NMR (CDCl₃): δ 7.99-6.81 (m, 10H), 4.15(t, J=5 Hz, 2H), 3.09 (m, 6H), 2.44 (m, 2H), 1.99-0.87 (m, 16H).

Theor. C₂₆H.₃₄ N₂ O₂.HCl.1/2 H₂O: C, 69.08; H, 8.03; N, 6.19. Found: C,68.89; H, 7.92; N, 6.24.

EXAMPLE 2 (E)-2-[2-(4-Dibutylaminopropoxyphenyl)ethenyl]benzothiazole

The title compound was prepared in accordance with Example 1 startingwith 4-chloropropoxybenzaldehyde (17.0 g, 86 mmol) and using2-methylbenzothiazole (11 ml, 86 mmol) in place of 2-methylbenzoxazoleto give 25.0 g (89% yield) of(E)-2-[2-(4-chloropropoxyphenyl)ethenyl]benzothiazole (F) as a yellowsolid, mp 97°-99° C. ¹NMR (CDCl₃): δ 8.15-6.91 (m, 10H), 4.15 (t, J=5.2Hz, 2H), 3.81 (t, J=5.2 Hz, 2H), 2.21 (m, 2H).

Reaction of this product (10.0 g, 30 mmol) with dibutylamine produced8.4 g (66% yield) of the free base of the title compound which wasconverted to the HCl salt, mp 181°-182° C. IR(KBr): 3400, 1595 cm⁻¹ MS:422(M⁺). ¹H NMR (CDCl₃): δ 7.88-6.81 (m, 10H), 4.12 (t, J=5.3 Hz, 2H),3.02-2.59 (m, 6H), 2.25-0.84 (m, 16H).

Theor. C₂₆H₃₄ N₂ OS.2HCl.2H₂ O: C, 58.75; H, 7.58; N, 6.10. Found: C,58.52; H, 7.14; N, 5.26.

EXAMPLE 3

(E)-2-[2-(4-Piperidinopropoxyphenyl)ethenyl]benzothiazole K_(i)=15 nM

The procedure of Example 2 was followed starting with (F) of Example 2(3.0 g, 9.8 mmol) and using piperidine in place of dibutylamine toproduce 1.9 g (51% yield) of the free base of the named compound whichwas converted to the HCl salt, mp 215°-217° C. IR(KBr): 3400,1595 cm⁻¹.MS: 379(MH⁺). ¹H NMR (CD₃ OD): δ 7.64-6.48 (m, 10H), 3.72 (t, J=5.2 Hz,2H), 2.65 (m, 6H), 1.98 (m, 2H), 1.32 (m, 6H).

Theor. C₂₃H₂₆ N₂ OS.1HCl.3/2H₂ O: C, 62.49; H, 6.84; N, 6.34. Found: C,62.53; H, 6.94; N, 6.26.

EXAMPLE 4

(E)-2-[2-[4-(3-Piperidinopropoxy)phenyl]ethenyl]benzoxazole K_(i)=13 nM

The procedure of Example 1 was followed starting with (C) of Example 1(2.0 g, 6.4 mmol) and using piperidine in place of dibutylamine toproduce 1.1 g, (41% yield) of the named compound as the HCl salt, mp127°-128° C. IR(KBr): 3400,1600 cm⁻¹. MS: 363(MH⁺). ¹H NMR (CD₃ OD): δ7.89-6.81 (m, 10H), 4.24 (t, J=5.5 Hz, 2H), 2.65 (m, 6H), 1.75 (m, 8H).

Theor. C₂₃H₂₆ N₂ O₂.HCl.H₂ O: C, 66.26; H, 6.77; N, 6.72. Found: C,66.01; H, 6.92; N, 6.98.

EXAMPLE 5 (E)-2-[2-(4-Dibutylaminobutoxyphenyl)ethenyl]benzoxazole

The procedure of Example 1 was followed with p-hydroxybenzaldehyde (5.0g, 41 mmol) and using 1-bromo-4-chlorobutane (9.5 ml, 82 mmol) in placeof 1-bromo-3-chloropropane to give 8.9 g (97% yield) of4-chlorobutoxy-benzaldehyde. ¹H NMR (CDCl₃) δ 9.85 (s, 1H), 7.82 (d,J=8.1 Hz, 2H), 6.99 (d, J=8.1 Hz, 2H), 4.04 (t, J=5.3 Hz, 2H), 3.59 (t,J=5.3 Hz, 2H), 1.91 (m, 4H).

Condensation of this product (4.0 g, 19 mmol) with 2-methylbenzoxazole(2.3 ml, 19 mmol) gave(E)-2-[2-(4-chlorobutoxyphenyl)ethenyl]benzoxazole (D) (4.5 g, 72%yield) as an off-white solid, mp 92°-93° C. ¹H NMR (CDCl₃): δ 7.88-6.81(m, 10H), 4.08 (t, J=5.1 Hz, 2H), 3.34 (t, J=5.3 Hz, 2H), 2.55 (m, 4H).

Reaction of this product (3.0 g, 9.1 mmol) with dibutylamine producedthe named compound (0.4 g, 11% yield) which was converted to the HClsalt, mp 172°-174° C. IR(KBr): 3400, 1600 cm⁻¹. MS: 421(MH⁺). ¹H NMR(CD₃ OD):δ 7.82-6.85 (m, 10H), 4.02 (t, J=5.2 Hz, 2H), 3.11 (m, 6H),1.98-0.84 (m, 18H).

Theor. C₂₇H₃₆ N₂ O₂HCl.H₂ O: C, 68.26; H, 8.27; N, 5.6. Found: C, 68.31;H, 7.91; N, 5.48.

EXAMPLE 6

(E)-2-[2-(4-Piperidinobutoxyphenyl)ethenyl]benzoxazole K_(i)=34 nM

The title compound was prepared as described in Example 5 starting with(D) of Example 5 (2.5 g, 7.6 mmmol) and using piperidine in place ofdibutylamine to produce 1.2 g (42% yield) of the title compound as theHCl salt, mp 230°-232° C. IR(KBr): 1600 cm⁻¹. MS: 377(MH⁺). ¹H NMR(DMSO): δ 7.91-6.95 (m, 10H), 3.99 (t, J=5.2 Hz, 2H), 3.10 (m, 6H), 1.75(m, 10H).

Theor. C₂₄H₂₈ N₂ O₂.HCl: C, 69.80; H, 7.08; N, 6.78. Found: C, 70.12; H,7.09; N, 6.93.

EXAMPLE 7

(E)-2-[2-(4-Diethylaminobutoxyphenyl)ethenyl]benzoxazole K_(i)=48 nM

The procedure of Example 5 was followed starting with (D) of Example 5(2.5 g, 7.6 mmol) and using diethylamine in place of dibutylamine toproduce 0.32 g (12% yield) of the named compound as the HCl salt, mp219°-220° C. IR(KBr): 3400, 1600 cm⁻¹. MS: 365(MH⁺). ¹H NMR (CDCl₃): δ8.25-6.82 (m, 10H), 4.02 (t, J=5.4 Hz, 2H), 3.14 (m, 6H), 1.99 (m, 4H),1.36 (m, 6H).

Theor. C₂₃H₂₈ N₂ O₃.HCl.H₂ O: C, 65.94; H, 7.46; N, 6.69. Found: C,66.12; H, 7.25; N, 6.57.

EXAMPLE 8

(E)-2-[2-(4-Diethylaminopropoxyphenyl)ethenyl]benzoxazole K_(i)=31 nM

The title compound was prepared as described in Example 1 starting with(C) of Example 1 (2.0 g, 6.4 mmol) and using diethylamine in place ofdibutylamine to produce 2.8 g (85% yield) diethylamine in place ofdibutylamine to produce 2.8 g (85% yield) of the title compound as theHCl salt, mp 225°-226° C. IR(KBr): 1600 cm⁻¹. MS: 351(MH⁺). ¹H NMR (CD₃OD): δ 7.99-6.81 (m, 10H), 4.24 (t, J=5.7 Hz, 2H), 3.09 (m, 6H), 2.44(m, 2H), 0.87 (m, 6H).

Theor. C₂₂H₂₆ N₂ O₂.HCl: C, 68.29; H, 7.03; N, 7.24. Found: C, 68.34; H,7.34; N, 6.91.

EXAMPLE 9

(E)-2-[2-(4-Pyrrolinobutoxyphenyl)ethenyl]benzoxazole K_(i)=17 nM

The title compound was prepared as described in Example 5 starting with(D) of Example 5 (3.0 g, 9.1 mmol) and using pyrrolidine in place ofdibutylamine to produce 1.8 g (55% yield) of the title compound as theHCl salt, mp 229°-232° C. IR(KBr): 3400, 1600 cm⁻¹. MS: 363(MH+). ¹H NMR(CD₃ OD): δ 7.91-6.87 (m, 10H), 4.04 (t, J=5.2 Hz, 2H), 3.21 (m, 6H),1.99 (m, 8H).

Theor. C₂₃H₂₆ N₂ O₂.HCl.H₂ O: C, 65.25; H, 7.01; N, 6.72. Found: C,65.48; H, 7.24; N, 6.99.

EXAMPLE 10 E)-2-[2-(4-Dibutylaminobutoxyphenyl)ethenyl]benzoxazole

The procedure of Example 1 was followed with p-hydroxybenzaldehyde (5.0g, 41 mmol) and using 1-bromo-4-chlorobutane (9.5 ml, 82 mmol) in placeof 1-bromo-3-chloropropane to give 8.9 g (97% yield) of4-chlorobutoxybenzaldehyde. ¹H NMR (CDCl₃) δ 9.85 (s, 1H), 7.82 (d,J=8.1 Hz, 2H), 6.99 (d, J=8.1 Hz, 2H), 4.04 (t, J=5.3 Hz, 2H), 3.59 (t,J=5.3 Hz, 2H), 1.91 (m, 4H).

Condensation of this product (4.0 g, 19 mmol) with 2-methylbenzoxazole(2.3 ml, 19 mmol) gave(E)-2-[2-(4-chlorobutoxyphenyl)ethenyl]benzoxazole (D) (4.5 g, 72%yield) as an off-white solid, mp 92°-93° C. ¹H NMR (CDCl₃): δ 7.88-6.81(m, 10H), 4.08 (t, J=5.1 Hz, 2H), 3.34 (t, J=5.3 Hz, 2H), 2.55 (m, 4H).

Reaction of this product (3.0 g, 9.1 mmol) with dibutylamine producedthe named compound (0.4 g, 11% yield) which was converted to the HClsalt, mp 172°-174° C. IR(KBr): 3400, 1600 cm⁻¹. MS: 421(MH⁺). ¹H NMR(CD₃ OD): δ 7.82-6.85 (m, 10H), 4.02 (t, J=5.2 Hz, 2H), 3.11 (m, 6H),1.98-0.84 (m, 18H).

Theor. C₂₇H₃₆ N₂ O₂.HCl.H₂O: C, 68.26; H, 8.27; N, 5.6. Found: C, 68.31;H, 7.91; N, 5.48.

EXAMPLE 11

2-(4-Dipropylaminopropoxyphenyl)benzothiazole K_(i)=173 nM

The title compound was prepared as described in Example 43 of U.S. Pat.No. 4,861,897 starting with (I) of Example 43 (2.0 g, 6.3 mmol) andusing dipropylamine in place of dibutylamine to produce 0.41 g (19%yield) of the title compound as the HCl salt, mp 142°-143° C. IR(KBr):3400, 1600 cm⁻¹. MS: 369(MH⁺). ¹H NMR (CDCl₃): δ 8.19-6.95 (m, 8H), 4.19(t, J=5.1 Hz, 2H), 3.01 (m, 6H), 2.64-0.82 (m, 12H).

Theor. C₂₂H₂₈ N₂ OS.2HCl.1/2H₂ O: C, 58.65; H, 6.94; N, 6.22. Found: C,58.55; H, 6.85; N, 6.17.

EXAMPLE 12

(E)-2-[2-(3,5-Dimethyl-4-dipropylaminobutoxyphenyl)ethenyl]benzothiazoleK_(i)=1000 nM

The title compound was prepared according to the procedure of Example 5above using 4-chlorobutoxy-3, 5-dimethylbenzaldehyde in place of4-chlorobutoxybenzaldehyde and using 2-methylbenzothiazole in place of2-methylbenzoxazole. 4-Chlorobutoxy-3, 5-dimethylbenzaldehyde wasprepared from 3,5-dimethyl-4-hydroxybenzaldehyde according to theprocedure Example 1 above.

F. Biological Examples

In the present invention receptor binding was determined using the humanhistamine H₃ receptor (See Lovenberg et al Mol. Pharmacol. 1999, 1107).Screening using the human receptor is particularly important for theidentification of new therapies for the treatment of human disease.Conventional binding assays for example are determined using ratsynaptosomes (Garbarg et al J. Pharmacol. Exp. Ther. 1992, 263, 304),rat cortical membranes (West et al Mol. Pharmacol. 1990, 610), andguinea pig brain (Korte et al Biochem. Biophys. Res. Commun. 1990, 978).Only limited studies have been performed previously using human tissuebut these allude to significant differences in the pharmacology ofrodent and primate receptors (West et al Eur. J. Pharmacol. 1999, 233).

BIOLOGICAL EXAMPLE 1

1(A) Transfection of Cells with Human Histamine Receptor

A 10 cm tissue culture dish with a confluent monolayer of SK-N-MC cellswas split two days prior to transfection. Using sterile technique themedia was removed and the cells were detached from the dish by theaddition of trypsin. One fifth of the cells were then placed onto a new10 cm dish. Cells were grown in a 37° C. incubator with 5% CO₂ inMinimal Essential Media Eagle with 10% Fetal Bovine Serum. After twodays cells were approximately 80% confluent. These were removed from thedish with trypsin and pelleted in a clinical centrifuge. The pellet wasthen re-suspended in 400 μL complete media and transferred to anelectroporation cuvette with a 0.4 cm gap between the electrodes(Bio-Rad #165-2088). One microgram supercoiled H₃ receptor CDNA wasadded to the cells and mixed. The voltage for the electroporation wasset at 0.25 kV, the capacitance is set at 960 μF.

After electroporation the cells were diluted into 10 mL complete mediaand plated onto four 10 cm dishes. Due to the variability in theefficiency of electroporation, four different concentrations of cellswere plated. The ratios used were: 1:20, 1:10, and 1:5, with theremainder of the cells being added to the fourth dish. The cells wereallowed to recover for 24 hours before adding the selection media(complete media with 600 μg/ml G418). After 10 days dishes were analyzedfor surviving colonies of cells. Dishes with well-isolated colonies wereused. Cells from individual colonies were isolated and tested. SK-N-MCcells were used because they give efficient coupling for inhibition ofadenylate cyclase. The clones that gave the most robust inhibition ofadenylate cyclase in response to histamine were used for further study.

1(B) [³H]-N-methylhistamine Binding

Cell pellets from histamine H₃ receptor-expressing SK-N-MC cells werehomogenized in 20 mM TrisHCl/0.5 mM EDTA. Supernatants from a 800 g spinwere collected, reccentrifuged at 30,000 g for 30 minutes. Pellets wererehomogenized in 50 mM Tris/5 mM EDTA (pH 7.4). Membranes were incubatedwith 0.8 nM [³H]-N-methylhistamine plus/minus test compounds for 45minutes at 25° C. and harvested by rapid filtration over GF/C glassfiber filters (pretreated with 0.3% polyethylenimine) followed by fourwashes with ice cold buffer. Filters were dried, added to 4 mLscintillation cocktail and then counted on a liquid scintillationcounter. Non-specific binding was defined with 10 μM histamine accordingto Chen and Prusoff, Biochem. Pharmacol. 1973, 22:3099. K_(I) valueswere calculated based on a K_(D) of 800 pM and a ligand concentration([L]) of 800 pM according to the formula:

K_(I)=(IC₅₀)/(1+([L]/(K_(D))).

K_(I) values are provided in the examples above.

E. Other Embodiments

The features and advantages of the invention are apparent to one ofordinary skill in the art. Based on this disclosure, including thesummary, detailed description, background, examples, and claims, one ofordinary skill in the art will be able to make modifications andadaptations to various conditions and usages. These other embodimentsare also within the scope of the invention.

What is claimed is:
 1. A method for treating disorders mediated by thehistamine H₃ receptor in a patient, said method comprising administeringto the patient a pharmaceutically effective amount of compound offormula (I): R is O or S; R₁ is H, C₁₋₄ alkyl, C₁₋₄ alkoxy, Br, Cl, orI; R₂ and R₃ are H or —O—(CH₂)_(m)—NR₄R₅, wherein one of R₂ and R₃ is Hand the other is —O—(CH₂)_(m)—NR₄R₅, when R₃is —O—(CH₂)_(m)—NR₄R_(5,) R₂is independently H, halogen, C₁₋₄ alkyl, or C₁₋₄ alkoxy; R₄and R₅ arethe same or different, and are C₁₋₅ alkyl, C₃₋₆ cycloalkyl, benzyl,benzyl substituted by C₁₋₄ alkyl, C₁₋₄ alkoxy, Br, Cl, I, or R₄ and R₅together with n are piperidyl, pyrrolidyl, imidazolyl, or n-substitutedpiperazyl, wherein the substituent is C₁₋₄ alkyl, phenyl, or phenylsubstituted with C₁₋₃ alkoxy; n is 0 or1; m is 2-6; with the provisosthat when at least one of R and R₁ is Ar; and both of R and R₁ are notAr; or a pharmaceutically acceptable salt, ester, or amide thereof.
 2. Amethod of claim 1, wherein said condition is improved by administeringan H₃ antagonist.
 3. A method of claim 1, wherein said compound has aformula wherein R₂ is H.
 4. A method of claim 1, wherein said compoundhas a formula wherein R₃ is H.
 5. A method of claim 1, wherein R is O.6. A method of claim 5, wherein R₁ is H.
 7. A method of claim 1, whereinR is S.
 8. A method of claim 1, wherein n is
 1. 9. A method of claim 1,wherein said compound has a formula wherein NR₄R₅ is a cyclic radical.10. A method of claim 9, wherein said cyclic radical is piperidyl orpyrrolinyl.
 11. A method of claim 1, wherein said compound has a formulawherein each of R₄ and R₅ is independently selected from ethyl, propyl,isopropyl, and butyl.
 12. A method of claim 1, wherein m is 2, 3, or 4.13. A method of claim 12, wherein m is
 3. 14. A method of claim 1,wherein R₁ is H, methyl, methoxy, Br, Cl, or I; each of R₄ and R₅ isindependently selected from ethyl, propyl, isopropyl, and butyl, ortogether with N are piperidyl or pyrrolinyl; m is 3 or 4; and each R₂ isH, halogen, methyl, or methoxy.
 15. A method of claim 1, wherein saidcompound is selected from:(E)-2-[2-(4-Piperidinopropoxyphenyl)ethenyl]benzothiazole;(E)-2-[2-[4-(3-Piperidinopropoxy)phenyl]ethenyl]benzoxazole;(E)-2-[2-(4-Piperidinobutoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(4-Diethylaminobutoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(4-Diethylaminopropoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(4-Pyrrolinobutoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(4-Dibutylaminobutoxyphenyl)ethenyl]benzoxazole; and2-(4-Dipropylaminopropoxyphenyl)benzothiazole.
 16. A method of claim 1,wherein said compound is selected from(E)-2-[2-(3-dibutylaminopropoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-[3-[3-(4-methylpiperazino)propoxy]phenyl]ethenyl]-benzoxazole;(E)-2-[2-(3-dipropylaminopropoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(3-(1H-imidazol-1-yl)propoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(3-dipropylaminobutoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(3-(1H-imidazol-1-yl)butoxyphenyl)ethenyl]benzoxazole; and(E)-2-[2-(3-(1H-imidazol-1-yl)butoxyphenyl)ethenyl]-6-methoxybenzoxazole.17. A method of claim 1, wherein said compound is selected from(E)-2-[2-(4-dibutylaminopropoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(4-dipropylaminopropoxyphenyl)ethenyl]]benzoxazole;(E)-2-[2-(4-(1H-imidazol-1-yl)propoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(4-diethylaminopropoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-[4-(3-Piperidinopropoxy)phenyl]ethenyl]benzoxazole;(E)-2-[2-[4-(3-methylbenzylaminopropoxy)phenyl]ethenyl]-benzoxazole;(E)-2-[2-[4-(2-methoxyphenyl)piperazinopropoxyphenyl]ethenyl]-benzoxazole;(E)-2-[2-(4-dibutylaminopropoxyphenyl)ethenyl]-5-methylbenzoxazole;(E)-2-[2-(4-dibutylaminopropoxyphenyl)ethenyl]-6-methoxybenzoxazole;(E)-2-[2-(4-dibutylaminoethoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(4-dibutylaminobutoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(4-piperidinobutoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(4-dipropylaminobutoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(4-(1H-imidazol-1-yl)butoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(4-diethylaminobutoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(4-pyrrolidinobutoxyphenyl)ethenyl]benzoxazole; and(E)-2-[2-(4-(1H-imidazol-1-yl)pentoxyphenyl)ethenyl]benzoxazole.
 18. Amethod of claim 1, wherein said compound is selected from(E)-2-[2-(3-chloro4-dipropylaminobutoxyphenyl)ethenyl]-benzoxazole,(E)-2-[2-(3,5-dimethoxy-4-dipropylamino-propoxyphenyl)ethenyl]benzoxazole;and(E)-2-[2-(3,5-dimethyl-4-dipropylaminopropoxyphenyl)ethenyl]benzoxazole.19. A method for treating a patient with a central nervous systemdisorder, said method comprising administering to the patient apharmaceutically-effective amount of a compound of formula (I): R is Oor S; R₁ is H, C₁₋₄ alkyl, C₁₋₄ alkoxy, Br, Cl, or I; R₂ and R₃ are H or—O—(CH₂)_(m)—NR₄R₅, wherein one of R₂ and R₃ is H and the other is—O—(CH₂)_(m)—NR₄R₅, when R₃ is —O—(CH₂)_(m)—NR₄R₅, R₂ is independentlyH, halogen, C₁₋₄ alkyl, or C₁₋₄ alkoxy; R₄ and R₅ are the same ordifferent, and are C₁₋₅ alkyl, C₃₋₆ cycloalkyl, benzyl, benzylsubstituted by C₁₋₄ alkyl, C₁₋₄ alkoxy, Br, Cl, I, or R₄ and R₅ togetherwith N are piperidyl, pyrrolidyl, imidazolyl, or N-substitutedpiperazyl, wherein the substituent is C₁₋₄ alkyl, phenyl, or phenylsubstituted with C₁₋₃ alkoxy; n is 0 or 1; m is 2-6; with the provisosthat when at least one of R and R₁ is Ar; and both of R and R₁ are notAr; or a pharmaceutically acceptable salt, ester, or amide thereof. 20.A method of claim 19, wherein said compound has a formula wherein R₁ isH, methyl, methoxy, Br, Cl, or I; each of R₄ and R₅ is independentlyselected from ethyl, propyl, isopropyl, and butyl, or together with Nare piperidyl or pyrrolinyl; m is 3 or 4; and each R₂ is H, halogen,methyl, or methoxy.
 21. A method of claim 19, wherein said compound isselected from:(E)-2-[2-(4-Piperidinopropoxyphenyl)ethenyl]benzothiazole;(E)-2-[2-[4-(3-Piperidinopropoxy)phenyl]ethenyl]benzoxazole;(E)-2-[2-(4-Piperidinobutoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(4-Diethylaminobutoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(4-Diethylaminopropoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(4-Pyrrolinobutoxyphenyl)ethenyl]benzoxazole;E)-2-[2-(4-Dibutylaminobutoxyphenyl)ethenyl]benzoxazole;2-(4-Dipropylaminopropoxyphenyl)benzothiazole.
 22. A method of claim 19,wherein said central nervous system disorder is selected from sleep/wakedisorders, arousal/vigilance disorders, dementia, Alzheimer's disease,epilepsy, narcolepsy, eating disorders, motion sickness, vertigo,attention deficit hyperactivity disorder, learning and memory disorders,mild cognitive impairment, and schizophrenia.
 23. A method of claim 19,wherein said central nervous system disorder is selected fromAlzheimer's disease, epilepsy, eating disorders, learning and memorydisorders, migraine, sleep/wake disorders, allergic rhinitis,schizophrenia, mild cognitive impairment, and asthma.
 24. A method ofclaim 19, wherein said disorder is selected from sleep/wake disorders,arousal/vigilance disorders, attention deficit hyperactivity disorder,and learning and memory disorders.
 25. A method of claim 19, whereinsaid compound is selected from(E)-2-[2-(3-dibutylaminopropoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-[3-[3-(4-methylpiperazino)propoxy]phenyl]ethenyl]-benzoxazole;(E)-2-[2-(3-dipropylaminopropoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(3-(1H-imidazol-1-yl)propoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(3-dipropylaminobutoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(3-(1H-imidazol-1-yl)butoxyphenyl)ethenyl]benzoxazole; and(E)-2-[2-(3-(1H-imidazol-1-yl)butoxyphenyl)ethenyl]-6-methoxybenzoxazole.26. A method of claim 19, wherein said compound is selected from(E)-2-[2-(4-dibutylaminopropoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(4-dipropylaminopropoxyphenyl)ethenyl]]benzoxazole;(E)-2-[2-(4-(1H-imidazol-1-yl)propoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(4-diethylaminopropoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-[4-(3-Piperidinopropoxy)phenyl]ethenyl]benzoxazole;(E)-2-[2-[4-(3-methylbenzylaminopropoxy)phenyl]ethenyl]-benzoxazole;(E)-2-[2-[4-(2-methoxyphenyl)piperazinopropoxyphenyl]ethenyl]-benzoxazole;(E)-2-[2-(4-dibutylaminopropoxyphenyl)ethenyl]-5-methyl-benzoxazole;(E)-2-[2-(4-dibutylaminopropoxyphenyl)ethenyl]-6-methoxy-benzoxazole;(E)-2-[2-(4-dibutylaminoethoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(4-dibutylaminobutoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(4-piperidinobutoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(4-dipropylaminobutoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(4-(1H-imidazol-1-yl)butoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(4-diethylaminobutoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(4-pyrrolidinobutoxyphenyl)ethenyl]benzoxazole; and(E)-2-[2-(4-(1H-imidazol-1-yl)pentoxyphenyl)ethenyl]benzoxazole.
 27. Amethod of claim 19, wherein said compound is selected from(E)-2-[2-(3-chloro-4-dipropylaminobutoxyphenyl)ethenyl]-benzoxazole,(E)-2-[2-(3,5-dimethoxy-4-dipropylaminopropoxy-phenyl)ethenyl]benzoxazoleand(E)-2-[2-(3,5-dimethyl-4-dipropylaminopropoxyphenyl)ethenyl]benzoxazole.28. A method for treating a patient with an upper airway allergicresponse, said method comprising administering to the patient apharmaceutically-effective amount of a compound of formula (I): R is Oor S; R₁ is H, C₁₋₄ alkyl, C₁₋₄ alkoxy, Br, Cl, or I; R₂ and R₃ are H or—O—(CH₂)_(m)—NR₄R₅, wherein one of R₂ and R₃ is H and the other is—O—(CH₂)_(m)—NR₄R₅, when R₃ is —O—(CH₂)_(m)—NR₄R₅, R₂ is independentlyH, halogen, C₁₋₄ alkyl, or C₁₋₄ alkoxy; R₄ and R₅ are the same ordifferent, and are C₁₋₅ alkyl, C₃₋₆ cycloalkyl, benzyl, benzylsubstituted by C₁₋₄ alkyl, C₁₋₄ alkoxy, Br, Cl, I, or R₄ and R₅ togetherwith N are piperidyl, pyrrolidyl, imidazolyl, or N-substitutedpiperazyl, wherein the substituent is C₁₋₄ alkyl, phenyl, or phenylsubstituted with C₁₋₃ alkoxy; n is 0 or 1; m is 2-6; with the provisosthat when at least one of R and R₁ is Ar; and both of R and R₁ are notAr; or a pharmaceutically acceptable salt, ester, or amide thereof. 29.A method of claim 28, wherein R₁ is H, methyl, methoxy, Br, Cl, or I;each of R₄ and R₅ is independently selected from ethyl, propyl,isopropyl, and butyl, or together with N are piperidyl or pyrrolinyl; mis 3 or 4; and each R₂ is H, halogen, methyl, or methoxy.
 30. A methodof claim 28, wherein said compound is selected from:(E)-2-[2-(4-Piperidinopropoxyphenyl)ethenyl]benzothiazole;(E)-2-[2-[4-(3-Piperidinopropoxy)phenyl]ethenyl]benzoxazole;(E)-2-[2-(4-Piperidinobutoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(4-Diethylaminobutoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(4-Diethylaminopropoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(4-Pyrrolinobutoxyphenyl)ethenyl]benzoxazole;E)-2-[2-(4-Dibutylaminobutoxyphenyl)ethenyl]benzoxazole;2-(4-Dipropylaminopropoxyphenyl)benzothiazole.
 31. A method of claim 28,wherein said compound is selected from(E)-2-[2-(3-dibutylaminopropoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-[3-[3-(4-methylpiperazino)propoxy]phenyl]ethenyl]-benzoxazole;(E)-2-[2-(3-dipropylaminopropoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(3-(1H-imidazol-1-yl)propoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(3-dipropylaminobutoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(3-(1H-imidazol-1-yl)butoxyphenyl)ethenyl]benzoxazole; and(E)-2-[2-(3-(1H-imidazol-1-yl)butoxyphenyl)ethenyl]-6-methoxybenzoxazole.32. A method of claim 28, wherein said compound is selected from(E)-2-[2-(4-dibutylaminopropoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(4-dipropylaminopropoxyphenyl)ethenyl]]benzoxazole;(E)-2-[2-(4-(1H-imidazol-1-yl)propoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(4-diethylaminopropoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-[4-(3-Piperidinopropoxy)phenyl]ethenyl]benzoxazole;(E)-2-[2-[4-(3-methylbenzylaminopropoxy)phenyl]ethenyl]-benzoxazole;(E)-2-[2-[4-(2-methoxyphenyl)piperazinopropoxy-phenyl]ethenyl]benzoxazole;(E)-2-[2-(4-dibutylaminopropoxy-phenyl)ethenyl]-5-methylbenzoxazole;(E)-2-[2-(4-dibutylaminopropoxyphenyl)ethenyl]-6-methoxybenzoxazole;(E)-2-[2-(4-dibutylaminoethoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(4-dibutylaminobutoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(4-piperidinobutoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(4-dipropylaminobutoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(4-(1H-imidazol-1-yl)butoxyphenyl)ethenyl]benzoxazole;(E)-2-[2-(4-d iethylaminobutoxyph enyl )ethenyl] be nzoxazole;(E)-2-[2-(4-pyrrolidinobutoxyphenyl)ethenyl]benzoxazole; and(E)-2-[2-(4-(1H-imidazol-1-yl)pentoxyphenyl)ethenyl]benzoxazole.
 33. Amethod of claim 28, wherein said compound is selected from(E)-2-[2-(3-chloro-4-dipropylaminobutoxyphenyl)-ethenyl]benzoxazole,(E)-2-[2-(3,5-dimethoxy-4-dipropylaminopropoxyphenyl)ethenyl]benzoxazole;and(E)-2-[2-(3,5-dimethyl-4-dipropylaminopropoxyphenyl)ethenyl]-benzoxazole.